Download Overview of Chlorine Dioxide (ClO )

Overview of Chlorine Dioxide (ClO2)
The compound chlorine dioxide (ClO2), now commercially important, is not in fact a recent
discovery. The gas was first produced by Humphrey Davy in 1811 when reacting hydrochloric
acid with potassium chlorate. This yielded "euchlorine", as it was then termed. Watt and
Burgess, who invented alkaline pulp bleaching in 1834, mentioned euchlorine as a bleaching
agent in their first patent. Chlorine dioxide then became well known as a bleach and later a
disinfectant. Since the beginning of the twentieth century, when it was first used at a Spa in
Ostend, Belgium, ClO2 has been known as a powerful disinfectant of water. The production of
ClO2 from the chlorate is complicated however, and the gas is explosive, so that it could not be
easily utilized practically until the production of sodium chlorite by Olin Corporation in 1940.
Chlorine dioxide could now be released when necessary from the chlorite salt. In municipal
water supplies this is usually done by adding chlorine to the chlorite solution, and in the
laboratory by adding an acid to the chlorite solution. Alliger showed in 1978, 1,2 that ClO2 could
be applied topically by the individual user.
Although ClO2 is a strong oxidizing agent and a particularly fast disinfectant, there are no reports
in the scientific literature of toxicity by skin contact or ingestion, or moreover of mutagenicity. It
would seem that effective application of this compound as a topical medication for skin
diseases,3,4 as a disinfectant on food, as well as a cold sterilant on instruments and glassware, is
long overdue.
ClO2 in some respects is chemically similar to chlorine or hypochlorite, the familiar household
bleach. However, ClO2 reactions with other organic molecules are relatively limited as
compared to chlorine. When ClO2 is added to a system – whether a wound or a water supply –
more of the biocide is available for disinfection and not consumed by other materials.5,6 Until
1963 hypochlorite was a standard product of the British Pharmacopoeia (for skin medications),
and burn patients even now are bathed in hypochlorite solution at some U.S. burn centers.
However, for many reasons ClO2 makes a likely substitute for the better known hypochlorite
since it is far less toxic and irritating when applied to the human body. ClO2 for example, does
not hydrolyze to form HCl as does chlorine, but remains a true gas dissolved in solution. ClO2,
unlike chlorine or hypochlorite, does not form chlorinated hydrocarbons when in contact with
organic matter, or readily add to double bonds. This is a prime concern since many chlorinated
hydrocarbons are known to be carcinogenic. Of the amino acids, the building blocks of proteins,
only aromatic amino acids and those containing sulfur react with ClO2. When hypochlorite is
applied to the skin, nitrogen trichloride is formed, a compound which appears in trace quantities
but is toxic and irritating. Also, hypochlorite in swimming pool water produces chloramine, an
eye irritant, and in wastewater, chloroform. Lastly, unlike hypochlorite or chlorine, ClO2 can
treat water at about 10 ppm with no harmful effects to fish. The LC50 for rainbow trout at 96
hours is 290 ppm.7 For this reason ClO2, rather than chlorine, is favored in commercial aquarium
water, especially in mammal tanks.8
Residuals of available chlorine in effluents from sewage treatment plants, including the
hypochlorite ion and chloramines, adversely influence aquatic life in receiving waters --1
the potential adverse effects both on the public health and on aquatic ecosystems due to
increased exposure to chlorinated compounds suggests that the use of chlorine relative to
other available techniques for the treatment of sewage and other waste-waters must be
reevaluated.9
At the time of World War I, when Dakins Solution (0.5% hypochlorite) gained fairly wide
acceptance as a wound disinfectant, ClO2 was not similarly adopted as there was, again, no easy
way to produce the gas in small quantities, or to transport it. The application of ClO2 to the body
is still not practiced, nor does it seem particularly obvious that it can be. The gas needs to be
released or "activated", normally done with strong acids or chlorine just before use. This process
appears somewhat unattractive therefore as a disinfectant in the lab or as a home remedy for the
skin. Further, once ClO2 is activated, shelf life is normally on the order of hours.
{GRAPH NOT SHOWN}
DECAY OF CHLORINE DIOXIDE IN FRESHWATER
From: Development and Evaluation of an Ion Chromatographic Method for Measuring
Chlorite and Chlorate Anions in Bleached Kraft Mill Effluent, NCASL technical bulletin
#673, July 1994, p. 3
However, in dilute solutions, in a closed container and absence of light, ClO2 can remain stable
for long periods. This is especially the case in chilled water.
A new compound, DIOXIDERM (formerly CITRONEX) disinfectant gel, makes novel use of
ClO2 and is available as a "skin cream" in a two-part system.10 The amount to be applied is
mixed just before use, and the chlorine dioxide is released slowly. Because disinfection and
lesion response are so rapid, the needed extra step of mixing seems unimportant, especially when
treating diseases such as diabetic ulcers or pox lesions. Dual or co-dispensers simplify the
application. Similarly, a dual toothpaste and mouthwash, DIOXIBRITE and DIOXIRINSE are
now available which kill all bacteria and deodorize the mouth. DIOXIGUARD Liquid for
instrument and hospital application as well as general topical use, is a fast acting disinfectant.
The shelf life after combining the needed quantity is one day. DIOXIGUARD kills all bacteria,
viruses and fungi within one minute, including mycobacteria and amoeba.
WIDE USE OF CHLORINE DIOXIDE IN INDUSTRY
2
Paper mills in the U.S. generate an enormous quantity of ClO2, 500 tons daily for bleaching
pulp.11 Although more expensive than chlorine, it is the bleach material of choice because the
basic properties of cellulose are not altered. The textile industry applies ClO2 similarly, where
prevention of injury to the fibers is important. Both cellulosic and synthetic materials are
processed in this way, including cottons, acetates, rayons, polyesters, acrylics and nylons. Cotton
is not degraded because the oxidation reaction is highly selective toward lignin and hemicellulose
components of the fiber. ClO2 does not adversely effect old paper prints or drawings, and will
clean ancient documents without injury to fibers.
The first use of chlorine (Cl2) as a water treatment process in the U.S. occurred in Jersey City in
1908 12, and of chlorine dioxide, at Niagara Falls in 1944.13 ClO2 now purifies water in over 500
water treatment facilities in the U.S.14 and many more in Europe. Only chlorine dioxide among
the common water treatment disinfectants (ozone, chlorine, chloramine, and chlorine dioxide),
produces no signs of malignancy in test animals.15 ClO2 is often applied for water treatment
other than disinfection, for example, remedying difficult smell and taste problems. Phenols, in
particular, are quickly oxidized, and without odorous chlorophenols often produced by chlorine.
ClO2 is considered the best additive for oxidizing iron and manganese impurities in drinking
water, and for eliminating taste and odor due to algae.16 It also removes cyanides sulfides,
aldehydes and mercaptans. ClO2 as used in water disinfection is more sporicidal than Cl2 17 ,18 , a
more powerful inactivator of viruses19, and inactivator of cysts.20 In storm water overflow, ClO2
has proved active toward all viruses examined.21
Another application of ClO2 is in the bleaching of fats and flour.22
Extensive experience with chlorine dioxide bleaching of tallow (the fat
extracted from meat scraps and dead animals) has shown that this is a safe
chemical bleaching process. The chlorine dioxide selectively converts color
bodies to lighter colored ones without substantial attack on natural antioxidants
in the oil which protect it against aging and rancidity. Tallows bleached with
Chlorine dioxide meets the "Refine and Bleach Test", is color stable, and is
now in use for the manufacture of the highest-grade toilet soaps.23
Many nutrition and toxicology studies have been performed assessing chlorine dioxide's effect on
flour. Treatment of flour with 200 ppm, fed to rats, had no effect after several generations.24,25
Flour treated with up to 500 ppm (5 times the concentration in DioxiCure Gel) fed to puppies had
no untoward effect.26 Thirteen human subjects fed experimentally for six weeks with flour
products that were treated with doses up to 400 ppm had no detectable toxic symptoms.27 Flour
bleached with normal dosage is not reduced appreciably in nutritive value.28 Essential fatty acids
are generally not effected, but tocopherol and cystine are oxidized.29 Reactivities of 21 amino
acids with ClO2 were evaluated using an iodmetric assay, only 6 were found to be reactive at pH
6. They were cysteine, histidine, hydroxyproline, proline, tryptophan and tyrosine.76
3
Several other applications within the food industry have been described. The first reported use of
ClO2 in the canning industry was by Green Giant at LeSueur, Mn. more than 30 years ago. The
objective was to conserve water while at the same time control bacteria.30 When ClO2 rather
than chlorine is added to process waters recirculated to clean potatoes, starch by-product,
previously extracted for gluing cartons, is upgraded to food grade level and a higher market
value. Also, the fresh water need is reduced 25%. In this particular process 10 ppm ClO2 is
added to the wash water in order to maintain a 1 ppm residual.31 Chlorine dioxide is excellent as
a commercial disinfectant in turkey egg sanitation, and its use does not modify the hatching
properties of the fertile eggs.32 The shelf life of tomatoes can be improved by treatment with
ClO2.33 ClO2 also finds application in bleaching cherries and as a teat dip for cows to prevent
mastitis. The FDA has recently permitted the use of ClO2 for disinfecting chickens, beef and
fruits and vegetables.
Masschelein, in his book Chlorine Dioxide, cites the following:
Chlorine dioxide destroys the microorganisms in fish, fruits and vegetables; and
the treatment can be carried out without altering the nutritive and organoleptic
qualities of the foodstuff. It will take place either by 30-minute immersion in an
aqueous solution of 50 to 1,000 mg/1 (50 to 1000ppm) of ClO2 or by exposure to
air containing 2,000 to 3,000 ppm of ClO2. This is a very favorable treatment for
the storage of frozen foods. Natural foods such as pepper may be sterilized by a
treatment with air containing 1,000 to 20,000 ppm of ClO2. The preservation of
melted cheese is facilitated by the addition of 100 to 300 mg/1 of ClO2 to the milk
used for its manufacture, and 100 to 400 mg/1 to its washing water. The bleaching
of oils and greases, particularly those used for alimentary needs, is carried out by a
maximum injection of 20,000 mg/1 of ClO2. The medicinal odor of cleaning
shrimps is eliminated by adding 40 mg/1 to the washing water. A dose of less
than 100 mg/1 of ClO2 does not seem to hinder the taste or nutritive value.34
The remaining or residual products on fruits and vegetables after treatment with ClO2 are
apparently chloride and a trace amount of chlorite.35 A recent patent by Frontier Pharmaceutical
involves the lowering of the chlorite residual, and describes a method for the release of ClO2 at
higher, more physiological pH.
Some industrial applications of ClO2 other than bleaching or disinfecting include: the treatment
of leather, where ClO2 oxidizes disulfide bridges of keratin; stabilization of vinyl and latex
enamels; additive in air pollution control for complexing impurities such as mercaptans and
aldehydes; controlling odors of fishmeal and rendering plant water effluents; an oxidant in the
preparation of vaccines 36 ,37 and neutralizing toxins 38; and a copper etchant in the manufacture
of electronic component parts.
4
DIFFERENCES WITH OTHER OXIDANTS
Although chlorine and chlorine dioxide are both strong oxidizing agents, they differ in reactions
with various organic and inorganic compounds. ClO2 for example, does not combine with
ammonia as does Cl2. Chlorine dioxide is a better disinfectant in the presence of organic matter,
and bacterial kill is not appreciably changed with change in pH. Hypochlorite has a higher
oxidation potential and is an indiscriminate "chlorinator", adding a permanent chlorine atom to
organic molecules. This unfortunately, produces a number of unwanted chlorinated
hydrocarbons such as chloroform and chlorophenol. Chemicals found in industrial waste
discharges for example, all react to produce chlorinated by-products that are hazardous to
health.39 ClO2, on the other hand, oxidizes (removes electrons) without adding an atom of its
own to the oxidized product. The pKa for the chlorite ion, chlorous acid equilibrium, is
extremely low at pH 1.8. This is different from the hypochlorous acid/hyopochlorite base ion
pair equilibrium found near neutrality, and indicates the chlorite ion will exist as the dominant
species in drinking water and in the human body.
When purifying water supplies, ClO2 combines with phenols particularly fast by attacking the
benzene ring. Odorless, tasteless products are formed directly, without intermediate compounds,
as is the case with chlorine.40 ClO2 may be more effective than copper sulfate in controlling
algae; it is believed to attack the pyrrole ring of the chlorophyll which cleaves the ring and leaves
the chlorophyll inactive. The reaction of ClO2 with algae, again, forms tasteless, odorless
products.
Olefins react much more rapidly with permangenate than with chlorine dioxide, whereas,
triethylamine is thousands of times more reactive with chlorine dioxide than with permanganate.
Unlike most other oxidizing compounds, ClO2, and its reduction product ClO2¯ , can act either as
oxidizing or reducing agents (NCASI No. 673). Under acid conditions hydrogen peroxide will
reduce ClO2 to form chlorous acid, but ClO2 also can be oxidized by chlorine to produce
chlorate, and by ozone to produce Cl2O6. ClO2¯ similarly can oxidize iodide to form iodine, or
be oxidized by hypochlorite ion to form chlorate. Combining ClO2 with blood causes
methemoglobin by oxidizing Fe3 to Fe2 in the red blood cell. Breathing ClO2 can have this
effect.
When ClO2 oxidizes organics, it usually takes in one electron and reduces to ClO2¯ . ClO2 can
oxidize some inorganics, like ferric oxide, remove 5 electrons rather than one, and reduce all the
way to chloride. The amount of electron exchange is the oxidizing capacity, not the redox
potential or driving force of the reaction.
5
ClO2 (aq) + e- = ClO2¯ where E° = 0.95V
When oxidizing organic molecules, there is no chlorine atom exchange to produce chlorinated
hydrocarbons.
CHEMICAL REACTIONS 41,42,43,44
Preparation of ClO2
l. Acidification of chlorite
H+ + NaClO2 → HClO2 + Na+
5HClO2 → 4ClO2 + HCl + 2H2O
2. Oxidation of chlorite by hypochlorite - for alkaline bleaching & water treatment
2NaClO2 + NaOCl + H2O → 2ClO2 + NaOH + HCl
3. Oxidation of chlorite by chlorine
2NaClO2 + Cl2 → 2ClO2 + 2NaCl
4. Reduction of chlorate with sulfur dioxide - used in pulp bleaching
2NaClO3 + SO2 → 2ClO2 + Na2SO4
5. Oxidation of chlorite by persulfate
2NaClO2 + Na2S2O8 → 2ClO2 + 2Na2SO4
6. Reduction & acidification of chlorate by oxalic acid
2HClO3 + H2C2O4 → 2ClO2 + 2CO2 + 2H2O
To inhibit further oxidation, the following are good scavengers of ClO2: sulfamic acid,
sulfur dioxide, resorcinol, hydroquinone, sodium thiosulfate, sodium bisulfite, sodium sulfite,
sodium arsenite and plumbous oxide. Agents that reduce ClO2 completely to the chloride ion:
borohydride, iodide at pH 1, sulfurous acid, ferrous chloride manganese and vitamin C.
Ferrous chloride will eliminate chlorate.
{GRAPH NOT SHOWN}
UV-Vis absorption spectra showing the release of ClO2 from sodium chlorite at various pH values. Readings were
taken after 60 minutes at ambient temperature. The initial chlorite concentration was 112 ppm. Notice the loss of
chlorite at 262 nm as the pH is lowered, with the gain of ClO2 at 360 nm. There is little or no release of ClO2 above
pH 3.45
Inorganic Reactions:
6
l. For iodometric analysis
2ClO2 + 2I¯ → 2ClO2¯ + I2
2. Oxidation of iron
ClO2 + FeO + NaOH + H2O → Fe (OH)3 + NaClO2
3. Oxidation of manganese
2ClO2 + MnSO4 + 4NaOH → MnO2 + 2NaClO2 + Na2SO4 + 2H2O
4. Oxidation of sodium sulfide
2ClO2 + 2Na2S → 2NaCl + Na2SO4 + S
5. Oxidation of nitrogen oxide pollutant
2NO + ClO2 + H2O → NO2 + HNO3 + HCl
6. Gas phase reaction with flourine
F2 + 2ClO2 → 2FClO2
7. In alkaline solution
2ClO2 + 2OH¯ → ClO2¯ + ClO3¯ + H2O
8. Aluminum, magnesium, zinc & cadmium react with ClO2
M + xClO2 → M(ClO2)x
9. Disproportionation of chlorite depends upon chlorides
present, pH, and ratio of ingredients
4ClO2¯ + 4H+ → Cl- + 2ClO2 + ClO3¯ + 2H+ + H2O
5ClO ¯ + 4H+ → 4ClO + Cl ¯ + 2H O
2
2
2
l0. With hydrogen peroxide as a reducing agent in commercial
production of chlorite
2ClO2 + H2O2 + 2NaOH → 2NaClO2 + 2H2O + O2
11. A highly colored complex is formed when ClO2 is dissolved in an aqueous
solution of barium chlorite ClO2 + ClO2¯ → Cl2O4
Organic Reactions:
l. With organic compounds in water → aldehydes, carboxylic acids, ketones &
quinones
2. With olefins → aldehydes, epoxides, chlorohydrins, dichloro-derivatives, and
chloro-and unsaturated ketones.
3. With ethylenic double bonds → ketones, epoxides, alcohols
4. With benzene → no reaction
5. With toluene → Ch3, CH2Cl, CH2OH
6. With anthracene 45o → anthraquinone, l, 4-dichloroanthracene
7. With phenanthrene → diphenic acid, 9-chlorophenanthrene
8. With 3, 4-benzopyrene → quinones, traces of chlorinated benzopyrene
(no longer considered carcinogenic)
9. With carboxylic and sulfonic functions → no reaction
10. With aldehydes → carboxylic acids
7
11. With ketones → alcohols
12. With aliphatic amines
primary
→ slow or no reaction
secondary → slow or no reaction
tertiary
→ rupture of CN bond, no N-oxides formed
13. With triethylamine
H2O+(C2H5)3N + 2ClO2
→ (C2H5)2NH + 2ClO2 - + CH3CHO + 2H+
14. With phenol → P-benzoquinone, 2 chlorobenzoquinone
15. Excess ClO2 with phenol → maleic acid, oxalic acid
16. With thiophenols → sulfonic acids
17. With tocopherol → demethylated derivatives
18. With saturated acids → no reaction
19. With anhydrides → no reaction but catalyzes hydrolysis
20. With amino acids: glycine, leucine, serine, alanine, phenylalamine, valine,
hydroxyproline, phenylaminoacetec, aspartic, glutamic acids→ little, or no reaction
21. With amino acids containing sulfur → reactive
22. With methionine → sulfoxide → sulfone
23. With aromatic amino acids → reactive
24. With tyrosine → dopaquinone, dopachrome
25. With tryptophan → idoxyl, isatine, indigo red, trace chlorinated products
26. With thiamine → slow reaction
27. With keratin → hydrosoluble acids
28. With carbohydrates CHO and CH2OH → carboxylic functions
29. With vanillin pH4 → monomethyl ester, β-formylmuconic acid
30. With pectic acid → mucic acid, tartaric acid, galacturonic acid
31. With chlorophyll and plant dyes → color removed.
32. With latex and vinyl enamels → delays polymerization
33. With napthaline → no reaction
34. With ethanol → no reaction
35. With biacetyl → acetic acid, carbon dioxide
36. With 2,3-butaneodiol → acetic acid, carbon dioxide
37. With cyclohexene → aldehydes, carboxylic acids, epoxides, alcohols, halides,
dienes,
ketones
38. With maleic acid → no reaction
39. With fumaric acid → no reaction
40. With crotonic acid → no reaction
41. With cyanides → oxidized
42. With nitrites → oxidized
43. With sulfides → oxidized
Hydrocarbons of longer chain length than C8 are the most oxidizable by ClO2.46
The organic compounds most reactive with ClO2 are tertiary amines and phenols.
8
Unsaturated fatty acids and their esters are generally oxidized at the double bond.
ClO2 DOES NOT REACT WITH:
hippuric acid, cinnamic acid, betaine, creatine, alanine, phenylalanine, valine, leucine,
asparaginic acid, asparagine, glutaminic acid, serine, hydroxyproline, taurine, aliphatically
combined NH2 groups, amido and imido groups, HO groups in alcohols and HO acids, free or
esterified CO2H groups in mono and polybasic acids, nitrile groups, the CH2 groups in
homologous series, ring systems such as C6H6, C10H8, cyclohexane, and the salts of C5H5N,
quinoline and piperidine.
Most aliphatic and aromatic hydrocarbons do not react with ClO2 under normal water
treatment conditions, unless they contain specific reactive groups. Alcohols are resistant at
neutral pH, but under conditions of very low pH, high temperatures or high concentrations,
alcohols can react to produce their corresponding aldehydes or carboxylic acids.47
ClO2¯ , chlorite, the reduction product of ClO2, although a less powerful oxidant, is used to react
with many malodorous and highly toxic compounds such as unsaturated aldehydes, mercaptans,
thioethers, hydrogen sulfide, cyanide and nitrogen dioxide.
{GRAPH NOT SHOWN}
UV-Vis absortion spectra43 for:
• a commercial “stabilized chlorine dioxide oral rinse” at a concentration of 100 ppm chlorite at pH 6.5 (there is
no release of chlorine dioxide shown at 360 nm)
• a solution of sodium chlorite (ClO2¯ ) at 900 ppm in a phosphate buffer at pH 7
• a sodium chlorate (ClO3¯ ), at 900 ppm in a phosphate buffer at pH 7
{GRAPH NOT SHOWN}
Uv-Vis spectra of commercially available RetarDex® oral rinse utilizing “stabilized chlorine dioxide” at pH 6.5,
5.15, and 2.2. No ClO2 is evolved above pH 5 as shown at 360 nm.43
9
DIOXIDERM AND DIOXIGUARD EXPERIMENTAL DISINFECTANTS
Studies have shown DIOXIGUARD and DIOXIDERM, which are ClO2 or ClO2 complexes, to
be two of the fastest disinfectants.48 Bacteria, viruses and even fungi are killed in under 1
minute. This rate of deactivation includes mycobacteria, amoeba and spores (non dried). Two
questions immediately come to mind: How does DIOXICURE and DIOXIGUARD work? And,
why are they not toxic?
The method of chlorine dioxide bacterial kill at low ppm concentration seems to occur by the
disruption of protein synthesis and enzyme inactivation. 49 50 This is similar to the "time
honored", non-toxic mechanism of some common antibiotics. Oxidation of RNA and DNA do
not appear to take place, or are at least unimportant in the process. The site of action lies in the
soluble fraction of the cell; there appears to be no damage to whole structural components such
as ribosomes.51 Bringmann prepared electron micrographs of chlorine-treated cells immediately
after contact and observed no visual change in the cells, comparable to those killed with bromine
and iodine.52
At high ClO2 ppm, the method of rapid bacterial and viral kill appears to be the softening and
destroying of the cell wall or viral envelope.53 Human cells do not have cell walls and are
apparently unaffected. Our skin and bodies are likely protected from the general oxidative
effects of ClO2 by the many reducing agents in our cells and blood such as catalase, glutathione,
superoxide dismutase, vitamins E, C, A, B complex, uric acid, zinc and selenium. This is
probably the same internal protective mechanism that prevents damage from oxygen and free
radicals. Bacteria and viruses do not contain most of these reducing compounds.
Because ClO2 is a strong oxidizing agent and also itself a free radical, it quickly neutralizes
reactive molecules, and oxygen free-radicals that are produced in the body by macrophages such
•
•
as, NO , O2¯ , H2O2, HClO, and OH . These oxygen compounds are released in response to stress
or infection and cause inflammation and pain. Other potential irritants found in wounds are
similarly oxidized or reduced, such as leukotrienes, TNF, and interleukin. This neutralizing
property of ClO2, combined with its ability to completely disinfect, makes DIOXIDERM and
DIOXIGUARD ideal wound medications. Unlike iodine compounds, healing is not impeded.54
55
Veterinarians have been treating deep wounds and abscesses on tigers and elephants as well as
dogs and cats with outstanding success.56 DIOXIDERM GEL had similar striking results on
human (otherwise non-healing) diabetic ulcers.57 If our body could manage to manufacture
chlorine dioxide, as it does hypochlorite, hydrogen peroxide and superoxide, it would certainly
do so.
ClO2 is both a small molecule relative to common organic disinfectants and soluble. It is also a
gas and non-ionic. These properties no doubt facilitate the transporting process through the skin
or bacterial cell wall.
10
It is interesting to speculate on the formation of a ClO2 complex that may be involved in the
disinfection process. Electron configuration of the ClO2 molecule theoretically allows
combination. ClO2 will hydrate for example with water, and also can form compounds with the
chlorite ion [ClO2 • ClO2¯ ] ¯ .58 A highly colored complex, C2O4¯ , is formed when ClO2 is
dissolved in a solution of barium chlorite. There is evidence that more than one oxidant in a
disinfectant formula will act synergistically in deactivating microorganisms,59 for example
chlorous acid and chlorine dioxide.
As with household bleach, where hypochlorous acid and not chlorine is the active bacteria killer,
it may similarly be chlorous acid although quite unstable, and not chlorine dioxide, which is the
more active of the two species. Chlorous acid has a higher oxidation/reduction potential than
either ClO2 or hypochlorous acid. In Frontier's particular case, DIOXIDERM GEL maintains the
chlorous acid concentration since the unstable chlorous acid molecules formed when mixing A &
B are far less mobile within a viscous gel matrix. The chlorous molecules can not as easily
combine and evolve chlorine dioxide as would be the case in a liquid. The increase in chlorous
acid may be the reason that the gel form is the faster disinfectant on wounds and burns. The
chemical literature shows that a chlorite/acid mixture producing ClO2 has many more times the
oxidation power than ClO2 alone at similar pH.60 Interesting too, that the type of acid activator
producing the chlorous acid molecule can have an effect on the oxidizing strength of ClO2, or
ClO2 mixture.61
{GRAPH NOT SHOWN}
Comparison of the Disinfection Efficiencies
of ClO2 with Cl2 at pHs of 6.5 and 8.562
Comparison of the Dosage Required to Achieve
a 5-Log Reduction in Viable Bacteria at 60Second Contact Time63
NON-TOXICITY
Many evaluations have shown ClO2 compounds to be non-toxic. Five decades of use have not
indicated any adverse effects on health. The main areas of use have been disinfecting water
supplies, the elimination of unwanted tastes and odors, and bleaching in the pulp and paper and
textile industries. Toxicology tests include ingestion of ClO2 in drinking water, additions to
tissue culture, injections into the blood, seed disinfection64,65, insect egg disinfection, injections
under the skin of animals and into the brains of mice, burns administered to over 1500 rats, and
injections into the stalks of plants. "Standard" tests include, Ames Mutation, Chinese Hamster,
Rabbits Eye, Skin Abrasion, Pharmacodynamics and Teratology.66
In one tissue culture study, highly diluted DioxiDerm liquid was placed on CD4 cells infected
with H.I.V. 67. Viruses were inactivated inside the cell, as well as in the supernatant, and with
11
little damage to the CD4 cell itself. Daughter cells 6 days later, although not as viable as the
controls, were not infected. This is particularly impressive considering that most virucides are
cytotoxic, even at high dilutions. Similar efficacy and non toxicity was demonstrated on infected
cabbage seeds. 4000 seeds heavily infected with bacteria were soaked for about ½ hour in ClO2
disinfectant. No bacteria remained after this period, and the seeds then grew normally. 68
In order to reduce air and water pollution the EPA is proposing to substitute chlorine dioxide for
the usual chlorine bleach in all pulp and paper mills throughout the country. This effects 350
installations and costs the industry about $4 billion.69 With a prospect of changing from chlorine
to chlorine dioxide in our water supply, the EPA and American Water Works in the past have
commissioned over 100 papers and studies on the toxicity of ClO2. Many controlled animal
studies on the effects of ingesting sodium chlorite and chlorine dioxide have been conducted
from 1 to 1000 mg/L concentrations. Metabolically, both ClO2 and ClO2¯ are rapidly reduced
following ingestion. Radioactive chlorine tests show that most of the tagged chlorine is excreted
from the urine in the form of Cl- ion with a small amount of ClO2-. The no observed effect level,
NOEL, from animal ingestion studies involving ClO2 and ClO2¯ , ranges to 100 ppm 70,71,72, about
the concentration of Frontier's DioxiDerm gel for topical use. The half life for the elimination of
ClO2 and ClO2¯ from the plasma is less than half that of HOCl, hypochlorite.73
In one study, human volunteers drank ClO2 or ClO2¯ in solution up to 24 ppm and showed no
adverse effects.74 Several studies examined the effects on reproductive toxicity or teratology.
There is no evidence of fetal malformation or birth defects at ClO2 concentrations, in drinking as
well as skin route, up to 100 ppm.75 76 77 With prolonged feeding toxicity is produced mainly in
the red blood cell. Rats fed up to 1000 mg/l chronically for 6 months showed no significant
hematological changes. After 9 months, however, red blood cell counts, hematacrit and
hemoglobin were decreased in all treatment groups.
Lack of toxicity on a long term, but low level basis is dramatically illustrated by two separate
studies where rats,78 and honeybees,79 were fed ClO2 in high doses over a two year period. No ill
effects were noted with up to 100 ppm added to water supply.
In a skin sensitization study, ClO2 liquid and gel (similar to DIOXIDERM ) were injected
intradermally into guinea pigs, 10 times in about 3 weeks.80 No sensitivity reaction was
observed. At the site of continuous liquid injection, necrotic areas developed due to the low pH
of 2.7. This damage was reversible. The pH of Frontier's DIOXIDERM GEL and DIOXIDERM
Liquid, however, is much higher at pH 4, and would probably avoid this temporary damage. An
ocular irritation study in rabbits indicated redness in the conjunctivae after one hour, which
became normal after 24 hours. The cornea and iris remained unchanged after treatment.
Fast disinfection and non-toxicity are properties normally not found side-by-side in the same
compound. For example, formaldehyde and peracetic acid are strong and often used sterilants,
but they are also toxic and irritating. Because both speeds of deactivation and non-toxicity are
combined in DIOXIDERM biocides, new possibilities are opened for important skin products, as
well as commercial surface disinfection.
12
REFERENCES
1
Alliger Patents: # 4,084,747, # 4,330,531
Block, S.S., Disinfection, Sterilization and Preservation, 1983, 3rd edition, Lea & Febiger, 172
3
Kenyon A.J., DVM, PhD; Hamilton,S.G., B.A.; Douglas, D.M., B.S., Comparison of
Antipseudomonad Activity of Chlorine Dioxide/Chlorous Acid-Containing Gel with
Commercially Available Antiseptics, Amer. Journal of Vet. Research, 1986, 47, No. 5, 11011104,
4
Kenyon, A. J.; Hamilton, S. G.; Douglas, B.S.; Controlled Wound Repair in Guinea Pigs,
Using Antimicrobials that Alter Fibroplasia, Amer. J. of Vet. Res., 1986. 47, No. 1, pp 96-101
5
Ingols, R.S.; Ridenour, G.M., Chemical Properties of Chlorine Dioxide, J. Amer. Water Works
Assoc., 1940, 40, 1207
6
Sussman, S.; Ward, W.J., Microbiological Control with Chlorine Dioxide Helps Save Energy
MP, 16(7), 24, 1977
7
Acute Toxicity of Sodium Chlorite to Rainbow Trout, Toxicity, Test Report #BW-79-1-387,
Jan. 1979, E G & G Bionomics Aquatic Toxicology Laboratory, Wareham, Mass.
8
Dempster, R. P., Steinhart Aquarium Publications, Sept. 1970
9
Dugan, P. R., Use and Misuse of Chlorination for the Protection of Public Water
Supplies, ASM News, 1979, 44, No. 3, 101
10
Alliger, Patent 4,330, 531
11
Gall, R. J., Chlorine Dioxide, An Overview of its Preparation, Properties and Uses, Hooker
Chemicals & Plastic Corp., Niagra Falls, N. Y., 2
12
Dugan, P. R., Use and Misuse of Chlorination for the Protection of Public Water Supplies and
the Treatment of Wastewater, ASM News, 1978, 44, No. 3
13
White, G. C., Handbook of Chlorination, Van Nostrand Reinhold, New York, N. Y., 1972, 744
14
Harrington, R.M.; Romano, R.R.; Gates, D., Subchronic Toxicity of Sodium Chlorite in the
Rat, J. Am. College of Tox. 14 (1): 21-33
15
Ozone, Chlorine Dioxide and Chloramines as Alternatives to Chlorine for Disinfection of
Drinking Water, Water Supply Research, 1977, U.S. Environmental Protection Agency,
Cincinnati, Ohio
16
Ridenour, G.M.; Ingols, R.S.; Armbruster, E.H., Water Sewage Works 1960, 97:R83
17
Ibid 12
18
Berndt, H.; Linneweh, H.J., Arch. Hyg. Bacterial. 1969, 153, 41
19
Carlson, S.; Gas u., Wasserfach, 1965, 106, 32
20
Ingols, R.S., J. Inst. Water Engrs. 1950, 4:581
21
Smith, J.E.; McVey, J.L. Prepr. Pap. Natl. Meeting, Div. Envir. Chem.; Am. Chem. Soc.,
1973, 13:177; Chem. Abstr. 1975, 82:159955
22
FDA Reg: 21CFR 137.105: Other government Regs: FDA, Indirect Food Additives, 21CFR
175, 21CFR 178.1010(6) (34), 21CFR 186.1750. EPA, Safe Drinking Water Act, 40CFR 141,
40CFR141.72, 40CRF 141.74. Exemption from Tolerances on Raw Agricultural Commodities,
40CRF 180.1070
23
Upgrading Inedible Fats with Chlorine Dioxide, Olin Chemicals, Product Data Bulletin, Ad2127-974
24
Frazer, A.C., et al, J. Sci. Food Agr., 1956, 7, 464
25
Hutchinson, J. B., et al, J. Sci. Food Agr., 1964, 15, 725
2
13
26
Nakamura, F. I.; Morris, M. L., Cereal Chemical, 1949, 26, 50120
Newell, G. W., Cereal Chemical, 1949, 26:160
28
Graham, W. D. et al, J. Pharm. Pharmocol., 1954, 6, 534
29
Moran, T.; Pace, J.; McDermott, E.E., Nature, 1953, 171, 103
30
Field Report, Chlorine Dioxide Gains Favor as Effective Sanitizer, Food Engineering, March
1977
31
Bruce, D.J.; Stevens, P.B, Chlorine Dioxide Key to Successful Retrograde Water System,
Food Processing, April 1977
32
Ernst, R.A., et al, Poult Sci., 1974, 53, 14926
33
Rahman, R.A. et al, U. S. Natl. Tech. Inform. Serv., 1974, Ref. No. 746, 254, Chem. Abstr.,
vol. 78: 28144, 1973
34
Masschelein, W. J., Chlorine Dioxide, Ann Arbor Science, 1979, 172
35
Thomas, R., Use of ClO2 in Water Treatment of Fruits and Vegetables, FDA GRAS petition
3G0020, 1979
36
Weislow, O. S.; Wheelock, F., Suppression of Established Friend Virus Leukemia by Statolon:
Potentiation of Statolon's Leukemosuppressive Activity by Chlorite-Oxidized Oxyamylose,
Infection & Immunity, Jan. 1979, 129-136
37
Hermon, O.S.; Janis, B.; Levy, H.B., Post-Exposure Prophylaxis of Murine Rabies with
Polyuinosinic-Polycytidylic Acid and Chlorite-Oxidized Amylose, Antimicrobial Agents and
Chemotherapy, 1974, 507-511
38
Brazis, A. R., et al, J. Amer. Water Works Assoc., 1959, 51, 902
39
Ibid., 5, 100
40
Stevens, A.; Seeger, D.; Slocum, C., Products of Chlorine Dioxide Treatment of Organic
Materials in Water, Water Supply Research Div., U. S. Environmental Protection Agency,
Cincinnati, Ohio, 1977, 9
41
Ozone, Chlorine Dioxide and Chloramines as Alternatives to Chlorine for Disinfection of
Drinking Water, Water Supply Research, 1977, U.S. Environmental Protection Agency,
Cincinnati, Ohio
42
Masschelein, W. J., Chlorine Dioxide, 1979, Ann Arbor Sceince Pulbishers, Inc.
43
Gordon, G.; Kieffer, R.; Rosenblatt, D., The Chemistry of Chlorine Dioxide, Progress in
Inorganic Chemistry, Wiley-Interscience Publishers, 1972 15, 201-286
44
Ibid., 9, 612-631
45
Lynch, E.; Sheerin, A.; Claxson, A.W.; Atherton, M.D.; Rhodes, C.J.; Silwood, C.J.L.;
Naughton, D.P.; Grootveld, M. Free Rad. Res., 1997, 26, 209-234
46
Gordon, G., Kieffer, R. & Rosenblatt, D., The Chemistry of Chlorine Dioxide, Progress in
Inorganic Chemistry, Wiley-Interscience Publishers, 1972, 37, 60
47
Harrington, R. M., Gates, D., and Romano,R.R., A Review of the Uses Chemistry and Health
Effects of Chlorine Dioxide and the Chlorite Ion. Chlorine Dioxide Panel of the Chemical
Manufacturers Association, Washington, D.C., Apr. 1989. 15
48
Evaluations available by Nelson Labs., BioScience Labs., Liuzzi Microbiology Labs., and the
University of Tennessee Inst. of Agr.
49
Benarde, M. A.; Snow, B. W.; Olivieri, V. P.; Davidson, B., Kinetics and Mechanism of
Bacterial Disinfection of Chlorine Dioxide, Appl. Miocrobiol., 1957, 15, 257-265
27
14
50
Scatina, J.; Abdel-Rahman, M. The Inhibitory Effect of Alcide, an Antimicrobial Drug, on
Protein Synthesis in E. Coli, J Appl. Tox., 1985, 5, 6,
51
Olivieri, V., Chlorine Dioxide and Protein Synthesis, 1968, Master's Degree Thesis, West
Virginia University
52
Bringmann, G., Electron Microscopic Findings of the Action of Chlorine, Bromine, Iodine,
Copper, Silver and Hydrogen Peroxide on E. coli; Z. Hyg. Infektionskrankh, 1953, 138, 156-166
53
E. M. Photos supplied by Frontier Research, Inc. on request
54
Kenyon, A.J.; Hamilton, S., Wound Healing Studied with Alcide: a Topical Sterilant, Amer.
Society of Biol. Chemists 74th Annual Meeting, San Francisco, CA June 5-9 1983.
55
Kenyon, A.J.; Hamilton, S.G.; Douglas, D.M., Controlled Wound Repair By Anitimicrobials
That Alter Fibroplasia, Amer Assn. For Laboratory Animal Science, 34th Annual Session Nov. 611, 1983.
56
Veterinary reports supplied by Arco Research, Inc. upon request.
57
Reports available from Frontier Pharmaceutical, Inc.., 135 Spagnoli Rd. Melville, N.Y.
11747, tel. 631-777-1420, fax 631-777-1422
58
Ibid., 37
59
White, J.F.; Taylor, M.C.; Vincent, G.P., Chemistry of Chlorites, Industrial and Engineering
Chemistry. July, 1942, 789
60
Ibid., 51
61
Paluch, K.; Otto, J.; Starski, R., Investigations on Reactions of Chlorine Dioxide and Sodium
Chlorite with some Organic Compounds, Roczniki Chemii, Ann. Soc. Chim. Polonorum, 1974,
48, 1456
62
Bernarde, M.A.; Israel, B.M.; Olivieri, V.P.; Grandstrom, M.L., Efficiency of Chlorine Dioxide
as a Bactericide, Appl. Microbiol., Sept. 1965, 13, 776
63
Tanner, R.S., Comparative Testing and Evaluation of Hard-Surface Biocides, Jour. Ind.
Microbiology, 1989, 4, 145
64
Kawada, Hiroshi, Haneda, Tadayoshi, Soil Disinfection by Using Aqueous Chlorine Dioxide
Solutions, Patent application: JP95-111095 13 Apr 1995.
65
Report from Cornell, available from Frontier Pharmaceutical, Inc. upon request.
66
Ibid 49
67
Pontani, D.R., The In Vitro Effect of DioxiDerm on HIV,
68
Ibid 49
69
EPA Seeks Increase in Chlorate, O2 Use, Chemical Marketing Reporter, Nov 8, 1993
70
Bull, R. J. et al., Carcinogenic Activity of Reaction Products of Alternate Drinking Water
Disinfectants, Pharmacologist, 1979, 21, No.3, 218
71
Yokose, Y.; Uchida, K.; Nakae, D.; Shiraiwa, K.; Yamamoto, K.; Konishi, Y., Studies of
Carcinogenicity of Sodium Chlorite in B6C3F1 Mice, Env. Health Perspectives, 1987, 76, 205210
72
Final Draft Drinking Water Criteria Document on Chlorine Dioxide, Chlorite and Chlorate ,
EPA contract No. 68-C2-0139, Clement International Corp., March 31, 1994
73
Bull, R.J., Health Effects of Drinking Water Disinfectants and Disinfectant By-Products,
Envir. Sci. Tech., 1982, 16
74
Ibid., 41, 38
15
75
Suh, D.H.; Abdel-Rahman, M.S.; Bull, R.J., Effect of Chlorine Dioxide and Its Metabolites in
Drinking Water of Fetal Development in Rats, J. Appl. Toxicol. 1983, 3, 75-79
76
Tuthill, R.W.; Guisti, R.A.; Moore, G.S.; Calabrese, F.J., Health Effects Among Newborns
After Prenatal Exposure to ClO2 Disinfected Drinking Water, Envir. Health Perspect, 1982, 46,
39-45,
77
Gerges, A.-R., Skowronski, Effects of Alcide Gel on Fetal Development on Rats and Mice, J.
of Applied Tox., 1985, 5, No. 2
78
Haag, H.B., The Effects on Rats of Chromic Administration of Sodium Chlorite and
Chlorine Dioxide in Drinking Water, Med. Col. Virginia, Dept. Phys, & Pharm.,
Report to Olin Corp., February 7, 1949
79
Lockett, J., Oxodene: Longevity of Honey Bees, Journal of Econ. Entomology,
vol. 65,No. 1, Feb. 1972
80
Abdel Rahman, M.S., Gerges S.E., Alliger, H., Toxicity of Alcide, J. Applied
Toxicology, Vol. 2, No. 3, 1982
76
Tan, H.K., Wheeler, W.B., Wei, C.I., Reaction of chlorine dioxide with amino acids and
peptides, Mutation Research, 188: 259-266, 1987
16
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